Our objective is to provide a better understanding of the mechanisms leading to deterioration of glucose homeostasis in the elderly. We propose to undertake a set of integrated morphological, functional and biochemical studies of the endocrine pancreas and its autonomic innervation in the C57BL/6NNia mouse at 3, 6, 12, 18, 24 and 30 months of age in order to: 1) define age-correlated changes in the structure and function of the pancreatic islets in this animal model, and 2) determine whether age-correlated changes in pancreatic islet structure and function are due to altered autonomic input to the pancreas. The general morphology of the pancreatic islets will be assessed qualitatively using routine light microscopic techniques (aldehyde-fuchsin-trichrome). Pancreatic islet A, B, D and PP cells will be identified using immunocytochemistry. Cholinergic and adrenergic nerve fibers in the pancreas will be identified using acetylcholinesterase and glyoxylic acid-fluorescence histochemistry, respectively. The volume density of islets and the linear density of nerve fibers within the pancreas will be detemrined using stereological techniques (computer-assisted morphometry). Plasms insulin and glucagon responses to fasting, refeeding after a fast, and to glucose loads will be determined using radioimmunoassays. The activities of cholinergic and adrenergic nerves within the pancreas will be determined by measuring, in extracts of pancreatic tissues, the activities the biosynthetic enzymes cholineacetyl-transferase (CAT) and tyrosine hydroxylase (TOH), respectively. Data will be compared between age groups, using analysis of variance followed by Newman-Kuels tests to determine the effect of age on each parameter measured.